Transthyretin (TTR) is a homotetrameric protein composed of 127-amino acid, 14 kDa monomeric subunits. TTR is also known as CTS, HsT2651, PALB, prealbumin, and TBPA. TTR is synthesized in the liver, choroid plexus and retinal pigment epithelium for secretion into blood, cerebrospinal fluid (CSF), and the eye, respectively. In the blood, TTR serves as a carrier for the retinol-binding protein-retinol (vitamin A) complex, whereas in CSF and the eye, it carries both thyroxine and holo retinol-binding protein. In its native state, TTR exists as a tetramer.
TTR is an amyloidogenic protein that can form fibrils and other aggregates. Rate-limiting TTR tetramer dissociation can generate dimers which subsequently can dissociate into monomers. These monomers can subsequently adopt misfolded conformations and aggregate into TTR oligomers and amyloid fibrils in a process known as amyloidogenesis. Mounting evidence indicates that the active aggregation of misfolded monomeric TTR or TTR amyloidogenesis is a root cause of TTR amyloid diseases.
The process of TTR amyloid fibril formation or amyloidogenesis is associated with a number of diseases, which present a significant burden on human health. For example, wild-type TTR amyloidogenesis is associated with senile systemic amyloidosis (SSA), a cardiomyopathy affecting up to 25% of the population above the age of 80. Another example of a TTR-related amyloid disease is the autosomal dominantly inherited disorder familial amyloid polyneuropathy (FAP). FAP is a relentless degenerative disease that strikes between the age 20-60 and causes progressive peripheral nerve degeneration, autonomic nervous system dysfunction, and in many individuals cardiomyopathy. Without a liver transplant, FAP is usually fatal within 10-12 years. Familial amyloid cardiomyopathy (FAC), another inherited TTR-aggregation-associated disease, can lead to congestive heart failure and death. There are now more than 100 TTR point mutations associated with the hereditary amyloid diseases. Many of these diseases are often misdiagnosed because their symptoms can be mistaken for other diseases. Misdiagnosis and the general lack of early diagnostic methods for the TTR-related amyloidoses currently present a significant roadblock to effective treatment, as irreversible degeneration has often occurred by the time treatment is initiated.